Current vaccines against Human Papillomavirus (HPV) are highly effective. Unfortunately, these vaccines, based on the virus-like particles (VLP) of the viral major capsid protein, L l , are type-specific, meaning that they provide protection against only a small subset of HPV types associated with cervical cancer. In contrast, antibodies that are specific for highly conserved epitopes within the viral minor capsid protein, L2, are able to neutralize a remarkably broad range of HPV types. Thus, a vaccine targeting L2 could be broadly protective against oncogenic HPV types. Although attempts have been made to create L2 peptidebased vaccines, L2 is poorly immunogenic. Therefore, novel vaccine strategies are required in order to create highly effective vaccines based on L2. The humoral immune system responds vigorously to antigens displayed in a dense, repetitive array, such as on the surface of viruses and VLPs. Correspondingly, VLPs can be used as molecular scaffolds to increase the immunogenicity of heterologous antigens. VLPs can be used to induce antibody responses against poorly immunogenic targets, and even self-antigens are immunogenic when presented at high density on VLPs. In this proposal we will develop new vaccines targeting L2 by using VLPs derived from RNA phage as our vaccine platform. In specific aim 1, we will exploit the chemical conjugation technologies at our disposal to target previously identified peptides derived from L2. In specific aim 2, we will use a new VLP-based phage display technology to design and identify new candidate vaccines. In specific aim 3, we will assess the effectiveness of a pulmonary vaccination strategy to induce systemic and mucosal immunity against established and novel immunogens, and assess whether vaccination provides protection from genital challenge with HPVs. These studies will draw heavily on facilities provided by Core B (the Viral Assay Core). Moreover, the in vivo genital challenge studies have significant synergy with Project 1 (PI: Michelle Ozbun).